Bacterial and viral infections among adults hospitalized with COVID‐19, COVID‐NET, 14 states, March 2020–April 2022

Abstract Background Bacterial and viral infections can occur with SARS‐CoV‐2 infection, but prevalence, risk factors, and associated clinical outcomes are not fully understood. Methods We used the Coronavirus Disease 2019‐Associated Hospitalization Surveillance Network (COVID‐NET), a population‐based surveillance system, to investigate the occurrence of bacterial and viral infections among hospitalized adults with laboratory‐confirmed SARS‐CoV‐2 infection between March 2020 and April 2022. Clinician‐driven testing for bacterial pathogens from sputum, deep respiratory, and sterile sites were included. The demographic and clinical features of those with and without bacterial infections were compared. We also describe the prevalence of viral pathogens including respiratory syncytial virus, rhinovirus/enterovirus, influenza, adenovirus, human metapneumovirus, parainfluenza viruses, and non‐SARS‐CoV‐2 endemic coronaviruses. Results Among 36 490 hospitalized adults with COVID‐19, 53.3% had bacterial cultures taken within 7 days of admission and 6.0% of these had a clinically relevant bacterial pathogen. After adjustment for demographic factors and co‐morbidities, bacterial infections in patients with COVID‐19 within 7 days of admission were associated with an adjusted relative risk of death 2.3 times that of patients with negative bacterial testing. Staphylococcus aureus and Gram‐negative rods were the most frequently isolated bacterial pathogens. Among hospitalized adults with COVID‐19, 2766 (7.6%) were tested for seven virus groups. A non‐SARS‐CoV‐2 virus was identified in 0.9% of tested patients. Conclusions Among patients with clinician‐driven testing, 6.0% of adults hospitalized with COVID‐19 were identified to have bacterial coinfections and 0.9% were identified to have viral coinfections; identification of a bacterial coinfection within 7 days of admission was associated with increased mortality.

bacterial testing. Staphylococcus aureus and Gram-negative rods were the most frequently isolated bacterial pathogens. Among hospitalized adults with COVID-19, 2766 (7.6%) were tested for seven virus groups. A non-SARS-CoV-2 virus was identified in 0.9% of tested patients.
Conclusions: Among patients with clinician-driven testing, 6.0% of adults hospitalized with COVID-19 were identified to have bacterial coinfections and 0.9% were identified to have viral coinfections; identification of a bacterial coinfection within 7 days of admission was associated with increased mortality. infections and can be associated with increased morbidity and mortality 1,2 but can also be incidental. 3 Polymicrobial respiratory infections may stem from compromised mucosal lung structure and altered immune responses after an initial infection. 4,5 Secondary bacterial infections are known complications of severe influenza infection 6 ; however, studies of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suggest that bacterial coinfection and secondary infections among patients with COVID-19 are relatively uncommon. 3,7,8 Population-based data are limited on the prevalence of bacterial and viral coinfections in adults with COVID-19.
We used data collected through Coronavirus Disease 2019-Associated Hospitalization Surveillance Network (COVID-NET), a large, geographically diverse US population-based surveillance platform, to investigate the proportion of viral and bacterial infections among hospitalized adults with laboratory-confirmed COVID-19. In this study, our objectives were to (1) compare demographic, radiographic and clinical features, and outcomes among those with bacterial infections, (2) characterize the microbial spectrum of bacterial infections, and (3) describe the prevalence of viral infections. Understanding the epidemiology of bacterial and viral infections in adults hospitalized with COVID-19 and the association with disease severity can inform testing for coinfections and approach to antimicrobial treatment.

| Study population
Data were collected through COVID-NET, 9 a population-based surveillance system including more than 250 acute-care hospitals across 99 counties in 14 states (California, Colorado, Connecticut, Georgia, Iowa, Maryland, Michigan, Minnesota, New Mexico, New York, Ohio, Oregon, Tennessee, and Utah) covering approximately 10% of the US population. COVID-NET captures laboratory confirmed COVID-19-associated hospitalizations, defined as any patient residing in the catchment areas with a positive SARS-CoV-2 test during hospitalization or during the 14 days prior to admission. A full case report form is completed on a representative sample of cases stratified by age group and site. For sample selection, random numbers were generated and assigned to each case as previously described. 10 Sampling weights are assigned based on the probability of selection. Trained staff collect demographic information, signs and symptoms, underlying comorbidities, chest imaging, viral and bacterial testing, and outcomes including need for mechanical ventilation, critical care, and death. Individuals with a positive SARS-CoV-2 test were included regardless of reason for admission.

| Bacterial pathogens
Adults 18 years or older hospitalized with COVID-19 during March 2020 and April 2022 and receiving any culture testing within 7 days of admission (including 7 days before or 7 days after) were included in this cross-sectional analysis of bacterial pathogens. Only pathogens from sterile or respiratory sites were included; cultures from the nasopharynx, urine, or superficial sites (e.g., wound cultures) were

| Data analysis
For bacterial infections, we examined characteristics of patients with and without culture testing. Among those with testing, we compared characteristics of those with and without detection of bacterial infections within 7 days before or after hospital admission. We used chi-square testing for categorical variables and Wilcoxon rank sum tests for continuous variables. We then quantified the most common organisms recovered by site. The same pathogen species and site was only counted once from an individual. We examined whether having a clinically relevant bacterial pathogen with SARS-CoV-2 infection was associated with worse outcomes including intensive care unit (ICU) admission, receiving invasive mechanical ventilation (IMV), or death during the hospitalization using multivariable logistic regression analysis with generalized estimating equations (GEE) and controlling for age, sex, race and ethnicity, underlying medical conditions, and time period.
Variables significant in bivariate analysis and considered to be relevant to the outcome were included. We present adjusted relative risks (RR) with 95% confidence intervals. A sensitivity analysis on the association of bacterial infection and death was completed excluding individuals with first positive culture on the second day of ICU admission or later. For each respiratory virus, we calculated the proportion of individuals testing positive among all hospitalized adults with COVID-19 who were tested. Due to low number of viral coinfections, additional multivariable analyses were not performed.
Analyses were performed using SAS (version 9.4; SAS Institute).
COVID-NET uses a sampling scheme and collects clinical data on a representative sample of hospitalized adults. 11 All findings are weighted to account for the probability of selection of the sampled patients and adjusted to account for charts with incomplete or missing data.
Unweighted counts and weighted percentages are reported except when indicated. The variance estimation was conducted using the Taylor series linearization method.  Figure 1A). Of these, 1140, (6.0%) had a bacterial pathogen identified. The percent of all sampled cases with bacterial testing ranged from 46.3% to 70.3% when examined quarterly, and culture testing generally decreased over time ( Figure S1). Individuals receiving any bacterial testing were more likely to have underlying conditions (92.1% vs. 81.9%, p < 0.0001), receive ICU level care (30.4% vs. 11.7%, p < 0.0001), and had higher mortality (14.3% vs. 5.1%, p < 0.0001) compared to those without bacterial testing (Table S1).

| Ethical review
Among those with a bacterial infection, individuals had a median of 1 bacterial infection; the median earliest specimen collection date was on the first day of admission (0.9, interquartile range 0. 4-5.0  The most commonly detected virus was RV/EV (0.6%) ( Table 3). There were two hospitalized adults with COVID-19, another respiratory virus, and a bacterial pathogen within 7 days.

| DISCUSSION
Using data from a representative sample of 36 490 cases from 311 292 hospitalized adults with laboratory-confirmed SARS-CoV-2 infection, 6.0% of those with bacterial cultures had evidence of infection with a potentially clinically relevant bacteria within 7 days of admission. Although bacterial infections were identified relatively infrequently during the first week of hospitalizations, among those F I G U R E 1 Flowchart of hospitalized adults in COVID-NET with bacterial and viral infections. Unweighted counts and weighted percentages are reported. The seven viral groups include respiratory syncytial virus, rhinovirus/enterovirus, influenza (subtypes A, B, or unspecified), adenovirus, human metapneumovirus (HMPV), parainfluenza (serotypes 1-4), and common human coronaviruses (229E, HKU1, NL63, OC43).
T A B L E 1 Baseline characteristics of hospitalized adults with COVID-19 and bacterial testing performed within 7 days of admission, COVID-NET March 2020-April 2022, stratified by presence of bacterial infections. Unweighted counts and weighted percentages are reported.  14.9 (11.8-18.5) 2339 12.8 (11.9-13.8)   T A B L E 2 Adjusted relative risk for death among adults hospitalized with COVID-19 who had bacterial testing performed within 7 days of admission, COVID-NET March 2020-April 2022.  visualization; writing-review and editing.